The present invention covers [8-(phenylsulfonyl)-3,8-diazabicyclo[3.2.1]oct-3-yl](1H-1,2,3-triazol-4-yl)methanone compounds of general formula (I) which inhibit the enzymatic activity of AKR1C3.
The Aldo-keto reductase family 1 member C3 (AKR1C3 also called type 5 17-beta-hydroxysteroid dehydrogenase (17-beta-HSD5)) is a member of the aldo-keto reductase (AKR) superfamily of enzymes, which reduce the aldehyde/keto group in steroid hormones to the corresponding alcohol and therefore play an important role in androgen-, progesterone-, and estrogene metabolism/activation/deactivation.
AKR1C3 possesses 3α-HSD (hydroxysteroid dehydrogenase activity), 17β-HSD, 20α-HSD and prostaglandin (PG) F synthase activities. It catalyzes the conversion of estrone (weak estrogenic activity) to estradiol (potent estrogenic activity), the conversion of progesterone (potent anti-estrogenic activity) to 20-alpha-hydroxyprogesterone (weak anti-estrogenic activity) and the conversion of androstenedione to testosterone (Labrie et al. Front Neuroendocrinol. 2001, 22(3):185-212). Furthermore AKR1C3 catalyzes the conversion of PGH2 to PGF2α and PGD2 to 11β-PGF2, both known to stimulate inflammation and proliferation. Furthermore AKR1C3 has also been shown to metabolize a broad spectrum of carbonyl compounds and xenobiotics, including clinically administered anthracyclines (Bains et al. J. Pharmacol Exp. Ther. 2010, 335: 533-545; Novona et al. Toxicol Lett. 2008, 181:1-6; Hofman et al. Toxicology and Applied Pharmacology 2014, 278: 238-248).
AKR1C3 plays a role in several pathologic conditions/diseases:
Endometrioses:
Endometriosis is a chronic, mainly estrogen-dependent inflammatory disease characterized by the presence of endometrial tissue outside the uterine cavity. Major symptoms of endometriosis are chronic pelvic pain and subfertility.
Estrogen (E2) deprivation is the clinically proven concept and the underlying primary mechanism of action for pharmacological treatment of endometriosis. Besides systemic estrogen levels, there is increasing evidence that locally derived estrogen contributes to the growth of endometriotic lesions. High intra-tissue estrogen concentrations in endometriotic lesions have recently been described, suggesting high local estrogen synthesis in endometriosis (Huhtinen et al. J Clin Endocrinol Metab. 2012, 97(11):4228-4235). Accordingly, inhibition of local E2 production in the endometriotic lesion is regarded as a highly attractive mechanism of action for the treatment of endometriosis.
AKR1C3 is strongly expressed in endometriotic lesions and only marginally detectable in the ovary (Smuc et al. Mol Cell Endocrinol. 2009, 301(1-2):59-64). In a concerted action with CYP19A1 (aromatase), AKR1C3 is expected to be a key enzyme in local E2 production in endometriotic lesions, generating a pro-estrogenic environment, thereby stimulating proliferation in estrogen-sensitive endometriotic cells. Inhibition of AKR1C3 should therefore result in decreased local intra-tissue E2 levels and thereby decreased proliferation of endometriotic lesions. Effects on ovarian estrogen production are not expected, since AKR1C3 is only marginally expressed in the ovary and 17βHSD1 is the dominant ovarian hydroxysteroid dehydrogenase.
AKR1C3 is also a PGF2a synthase and beside the upregulation of AKR1C3 in endometriotic lesions, it has been shown that levels of PGF2a were significantly higher in both the eutopic and ectopic endometria derived from women with peritoneal endometriosis than in similar tissues derived from women with ovarian endometrioma (Sinreih et al. Chemico-Biological Interactions 2015, 234:320-331). PGF2a in endometriotic tissues is expected contribute to inflammation, pain and proliferation in endometriosis patients and AKR1C3, expressed in endometriotic lesions, is expected to contribute to high local PGF2a level in endometriotic tissues.
AKR1C3 inhibition has the potential to relieve proliferation, pain and inflammation in endometriosis patients by locally reducing E2, testosterone and PGF2a levels in the endometriotic tissues.
Polycystic Ovary Syndrome (PCOS):
PCOS is a common endocrine disorder, affecting up to 10% of women of reproductive age. It is associated clinically with anovulatory infertility, dysfunctional bleeding, androgen excess, hyperinsulinemia and insulin resistance, obesity and metabolic syndrome (Dunaif et al. Endocrine Rev. 1997, 18:774-800). Four cardinal features of PCOS have been recognized by the Androgen Excess Society: ovulatory and menstrual dysfunction, biochemical hyperandrogenaemia, clinical hyperandrogonism (e.g. acne, hirsutism) and polycystic ovaries (Azziz et al. Clin Endocrinol Metab 2006, 91:4237-45). The vast majority of women with PCOS will present with clinical signs of hyperandrogonism, e.g. acne, hirsutism, or anovulation manifest by primary subfertility or oligomenorrhea (Legro et al. N Engl J Med 2014, 371:119-129). Women with PCOS are predisposed to glucose intolerance and metabolic syndrome (Taponen et al. J of Clin Endocrinology and Metabolism 2004, 89:2114-2118), with associated risk factors for cardiovascular disease and a likely increased risk in future cardiovascular events (Mani et al. Clin Endocrinol 2013, 78:926-934).
Hyperandrogonism, hirsutism and/or hyperandrogenaemia is the key component of the syndrome and is mandatory for the diagnosis of PCOS (Azziz et al. Clin Endocrinol Metab 2006, 91:4237-45). While serum testosterone is a key factor for biochemical assessment of hyperandrogenaemia, recently androstenedione was suggested as a more reliable marker of PCOS-related androgen excess, since androstenedione is circulating at high concentrations in PCOS women (Reilly et al. J Clin Endocrinol Metab 2014, jc20133399).
PCOS has traditionally been regarded as a disorder of the ovary (Franks et al. J Steroid Biochem Molecular Biology 1999, 69:269-272). However, increased focus on extra-ovarian and extra-adrenal androgen formation in PCOS has highlighted the role of peripheral tissues such as adipose androgen formation (Quinkler et al. J of Endocrinology 2004, 183:331-342).
AKR1C3 is an androgen-activating enzyme, known to predominantly convert androstenedione to testosterone. Upregulation of AKR1C3 in adipose tissue of PCOS patients has been described, indicating that ARK1C3 expression in adipose is significantly contributing to androgen formation for androstenedione in PCOS patients. It has in addition been shown that AKR1C3 expression in adipocytes is significantly increased by insulin, indicating that insulin, which is high in PCOS is able to drive adipose androgen formation by increasing AKR1C3 activity in female subcutaneous adipose tissue (O'Reilly et al. Lancet 2015, 385 Suppl 1:S16). AKR1C3 is also a PGF2a synthase and plays a suppressive role in the formation of endogenous ligands for the peroxisome proliferator-activated receptor γ (PPARgamma), which is a target for insulin-sensitizing drugs (Spiegelman et al. Diabetes 1998, 47:507-514).
Selective AKR1C3 inhibition might offer a novel therapeutic target to reduce androgen burden and improve the metabolic phenotype in PCOS. (O'Reilly M1, et al. Lancet. 2015 385 Suppl 1:S16.; Du et al. J Clin Endocrinol Metab. 2009, 94(7):2594-2601.)
Cancer:
AKR1C3 is overexpressed in numerous cancers, which includes those cancers of the prostate, breast, uterine, blood, lung, brain and kidney, such as endometrial carcinoma (T. L. Rizner et al., Mol Cell Endocrinol 2006 248(1-2), 126-135), lung carcinoma (Q. Lan et al., Carcinogenesis 2004, 25(11), 2177-2181), non-Hodgkin lymphoma (Q. Lan et al., Hum Genet 2007, 121(2), 161-168), bladder carcinoma (J. D. Figueroa, Carcinogenesis 2008, 29(10), 1955-1962), chronic myeloid leukaemia (J. Birthwistle, Mutat Res 2009, 662(1-2), 67-74), renal cell carcinoma (J. T. Azzarello, Int J Clin Exp Pathol 2009, 3(2), 147-155), breast cancer (M. C. Byrns, J Steroid Biochem Mol Biol 2010, 118(3), 177-187), whereas its upregulation frequently correlates with tumor invasiveness and aggressiveness (Azzarello et al. Int. J. Clin. Exp. Path. 2009, 3:147-155, Birtwistle et al. Mutat. Res. 2009, 662:67-74; Miller et al. Int. J. Clin. Exp. Path. 2012, 5:278-289). AKR1C3 is able to directly reduce estrone and progesterone to 17β-estradiol and 20α-hydroxyprogesterone, respectively, thereby potentiating this pro-proliferative signal (Smuc and Rizner, Chem Biol Interact. 2009, 178:228-33). Additionally, the prostaglandin F synthase activities of AKR1C3 catalyses the conversion of PGH2 to PGF2α and PGD2 to 11β-PGF2, both known to stimulate inflammation and proliferation. In the absence of AKR1C3 activity, PGD2 (instead of being converted to PGF2), spontaneously dehydrates and rearranges to form anti-proliferative and anti-inflammatory PGJ2 isomers, including 15d-PGJ2. In summary, AKR1C3 increases the proliferative PGF2 isomers and decreases antiproliferative PGJ2 products, and therefore AKR1C3 has the potential to impact both hormone-dependent and hormone-independent cancers. In breast cancer it is postulated that actions of AKR1C3 can produce prostaglandin F2 alpha (PTGFR) ligands whose activation results in carcinoma cell survival (Yoda T et al., (2015) Mol Cell Endocrinol. 15; 413:236-247).
Prostate Cancer:
Elevated expression of AKR1C3 has been associated with prostate cancer progression and aggressiveness (Stanbrough M et al. Cancer Res 2006, 66:2815-25; Wako K et al. J Clin Pathol. 2008, 61(4):448-54). In hormone-dependent prostate cancer, AKR1C3 converts androstenedione to testosterone, which, in turn, excessively activates androgen receptors and promotes tumor growth (Penning et al. Mol Cell Endocrinol. 2006, 248(1-2):182-91).
In Castration-Resistant Prostate Cancer (CRPC)
AKR1C3 is involved in intratumoral androgen biosynthesis—it facilitates the conversion of weak androgens androstenedione (A′ dione) and 5 α-androstanedione (5α-dione) to the more active androgens testosterone and DHT, respectively (Liu et al. Cancer Res. 2015, 75(7):1413-22; Fung et al. Endocr Relat Cancer 2006, 13(1), 169-180). Importantly, AKR1C3 expression has been shown to be increased in patients with CRPC compared with primary prostate cancer (Stanbrough et al. Cancer Res 2006, 66: 2815-2825; Hamid et al. Mol Med 2012, 18:1449-1455; Pfeiffer et al. Mol Med 2011, 17:657-664). A genetic polymorphism in the AKR1C3 gene coding for AKR1C3 was also shown to be an independent predictor of prostate cancer (Yu et al. PLoS One 2013, 8(1):e54627). Moreover, AKR1C3-dependent de novo androgen synthesis was suggested to be a potential mechanism of resistance to CYP17A1 inhibitors, such as abiraterone (Mostaghel et al. Clin Cancer Res 2011, 17:5913-5925; Cai et al. Cancer Res 2011, 71:6503-6513). Therefore, AKR1C3 may be a promising therapeutic target in patients with CRPC (Adeniji et al. J Steroid Biochem Mol Biol 2013, 137:136-149). An AKR1C3 inhibitor was tested in patients with metastatic castration-resistant prostate cancer in a multi-centre phase I/II study. However, the novel androgen biosynthesis inhibitor showed no relevant evidence of clinical activity (Loriot et al. Invest New Drugs 2014, 32:995-1004). Recent data are indicating that AKR1C3 activation in CRPC is a critical resistance mechanism associated with anti-androgen (enzalutamide) resistance. It could be shown that androgen precursors such as cholesterol, DHEA and progesterone, as well as androgens are highly upregulated in enzalutamide-resistant prostate cancer cells compared to the parental cells. The data suggest that inhibition of AKR1C3 pathways could act as an enzalutamide-sensitizing treatment and restore efficacy in patients with enzalutamide-resistant CRPC (Liu et al. Cancer Res. 2015, 75(7):1413-22). It is postulated that co-treatment with an AKR1C3 inhibitor will overcome enzalutamide resistance and improve survival of advanced prostate cancer patients (Thoma et al. Nature Reviews Urology 2015, 12:124).
Anthracycline Resistant Cancer:
Anthracyclines (or anthracycline antibiotics) are a class of drugs which are used in cancer chemotherapy and derived from Streptomyces bacterium Streptomyces peucetius var. caesius (Fujiwara et al. Critical Reviews in Biotechnology 1985, 3(2):133). These compounds are used to treat many cancers, including leukaemia's, lymphomas, breast, stomach, uterine, ovarian, bladder cancer, and lung cancers. The anthracyclines are among the most effective anticancer treatments ever developed. However, the clinical success of anthracyclines for cancer treatment is overshadowed by drug resistance. It has become widely accepted that the elevated enzymatic reduction of anthracyclines to their less potent secondary C13-hydroxy metabolites constitutes one of the mechanisms that cause anthracycline resistance in tumors (Gavelova et al., 2008 Chem. Biol. Interact 176, 9-18; Heibein et al. 2012 BMC Cancer 12, 381). Enzymatic metabolism, especially of doxorubicin is responsible for the cardiomyopathy observed upon doxorubicin chemotherapy. AKR1C3 was shown to be implicated in the metabolism of clinically administered anthracyclines such as doxorubicin and daunorubicin (Novotna et al. Toxicol. Letter 2008, 181:1-6).
In 2012, a correlation of an AKR1C3 genetic variant with doxorubicin pharmacodynamics has been shown in Asian breast cancer patients: one genetic variant was associated with longer progression-free survival and overall survival after doxorubicin-based therapy suggesting potential interaction with the doxorubicin metabolism (Voon et al. British J of Clin Pharmacology 2012, 75:1497-1505).
Recently it could be demonstrated that AKR1C3 contributes to the resistance of cancer cells to anthracycline treatment and therefore concomitant administration of a specific AKR1C3 inhibitor with anthracyclines could be an efficient strategy for the successful prevention and treatment of anthracycline resistant tumors (Hofman et al. Toxicology and Applied Pharmacology 2014, 278:238-248).
Atopic Dermatitis:
Challenge of atopic subjects with antigen caused the release of PGD2 and histamine showing that PGD2 contributes little to the immediate hypersensitivity reactions of human skin and that PGD2 is a lipid mediator that promotes skin inflammation in atopic dermatitis (AD) (Barr et al., Br J Pharmacol. 1988, 94:773-80; Satoh et al. J Immunol. 2006, 177:2621-9.; Shimura et al. Am J Pathol. 2010; 176:227-37). PGD2 is a relatively unstable pro-inflammatory mediator which spontaneously converts to the potent anti-inflammatory mediator 15d-PGJ2. That conversion is diverted by the metabolism of PGD2 to the pro-inflammatory 9α,11β-PGF2 by AKR1C3. (Mantel et al. Exp Dermatol. 2016, 25(1):38-43).
It was demonstrated that AKR1C3 is upregulated in human AD samples and a role for AKR1C3 in mediating inflammation in skin pathology, especially atopic dermatitis and in keloids has been postulated (Mantel et al. J Invest Dermatol. 2012, 132(4): 1103-1110) Mantel et al. Exp Dermatol. 2016, 25(1):38-43). AKR1C3 inhibition might be a novel option for treatment of AD and keloids.
Inflammation:
AKR1C3 is involved in prostaglandin biosynthesis, catalyzing the conversion of PGH2 to PGF2α and PGD2 to 11β-PGF2. It has been postulated that expression and upregulation of AKR1C3 supports inflammation by directly causing an increase in 9α,11β-PGF2 synthesis rates and diverting the spontaneous generation of the potent anti-inflammatory mediator 15d-PGJ2 (Mantel et al. J Invest Dermatol 2012, 132(4):1103-1110). This function of AKR1C3 has also been implicated in HL-60 cells (Desmond et al. Cancer Res 2003, 63:505-512) and in MCF-7 cells (Byrns et al. J Steroid Biochem Mol Biol 2010, 118:177-187). Inhibition of AKR1C3 is postulated to increase 15d-PGJ2, an anti-inflammatory lipid that mostly mediates its actions directly via activation of peroxisome proliferator-activated receptor γ (PPAR-γ) and/or inhibition of NF-κB signaling in immune cells (Maggi et al. Diabetes 2000, 49:346-355; Scher et al. Clinical Immunology 2005, 114:100-109). Previous data have shown that PPAR-γ activation attenuates allergen-induced inflammation in skin and lungs of mice (Ward et al. Carcinogenesis. 2006, 27(5):1074-80; Dahten et al. J Invest Dermatol. 2008, 128(9):2211-8.). This suggests a role for AKR1C3 inhibition in suppressing of inflammation.
Further Diseases
Furthermore AKR1C3 inhibitors have potential for the treatment of prostate hyperplasia (Roberts et al., Prostate 2006, 66(4), 392-404), hair loss (L. Colombe et al., Exp Dermatol 2007, 16(9), 762-769), adiposity (P. A. Svensson et al., Cell Mol Biol Lett 2008, 13(4), 599-613), premature sexual maturity (C. He, Hum Genet 2010, 128(5), 515-527) and chronic obstructive pulmonary disease (S. Pierrou, Am J Respir Crit Care 2007, 175(6), 577-586).
Inhibitors of AKR1C3 are described in the prior art: Flanagan et al. Bioorganic & Medicinal Chemistry 2014, 22:967-977, Jamieson et al. Journal of Medicinal Chemistry 2012, 55:7746-7758, WO 2013/059245, WO 2013/142390, WO 2014/039820, WO 2013/045407, WO 2014/128108 and WO 2014/009274.
Heinrich et al. European Journal of Medicinal Chemistry 2013, 62:738-744 relates to 1-(4-(piperidin-1-ylsulfonyl)phenyl)pyrrolidin-2-ones as inhibitors of AKR1C3.
WO 2007/111921 (Amgen) relates to 1-phenylsulfonyl-diaza heterocyclic amide compounds and their uses in methods for treating a condition or disorder responsive to the modulation of hydroxysteroid dehydrogenases (HSD's), mainly for the treatment of diabetis or obesity. Among other diseases endometriosis is also specified. 11betaHSD1, 11betaHSD2 and 17betaHSD3 are explicitly disclosed. It is shown that the disclosed examples inhibit 11 betaHSD1 with a IC50 ranging from <1 nM-1000 nM. However, inhibition or modulation of the enzymatic activity of AKR1C3 or other HSD's are not disclosed. WO 2007/111921 relates inter alia to piperazine compounds, e.g. compound number 4 of table 1. However, piperazines with an ethylene bridge between position 2 and 6 are not disclosed in WO 2007/111921.
WO 2007/103456 (Trimeris) relates to piperazine derivatives and to methods of using the same in the treatment of HIV infection and AIDS.
WO 2008/024284 (Merck) relates to sulfonylated piperazines as cannabinoid-1 receptor modulators.
However, the state of the art does not describe the [8-(phenylsulfonyl)-3,8-diazabicyclo[3.2.1]oct-3-yl](1H-1,2,3-triazol-4-yl)methanone compounds of general formula (I) of the present invention as described and defined herein.
It has now been found, and this constitutes the basis of the present invention, that the compounds of the present invention have surprising and advantageous properties.
In particular, the compounds of the present invention have surprisingly been found to effectively inhibit AKR1C3 for which data are given in biological experimental section and may therefore be used for the treatment or prophylaxis of AKR1C3 related disorders such as gynecological disorders particularly endometriosis-related and polycystic ovary syndrome-related gynecological disorders, conditions and diseases, metabolic disorders, hyperproliferative disorders, conditions and diseases, and inflammation disorders.
In accordance with a first aspect, the present invention covers compounds of general formula (I):
in which:    R1 represents hydrogen, halogen, C1-C3-alkyl, C1-C3-haloalkyl, C1-C3-alkoxy, C1-C3-haloalkoxy, nitro or cyano;    R2 represents hydrogen, halogen, C1-C3-alkyl, C1-C3-haloalkyl, C1-C3-alkoxy, C1-C3-haloalkoxy, nitro, cyano or SF5;    R3 represents hydrogen, halogen, C1-C3-alkyl, C1-C3-haloalkyl, C1-C3-alkoxy, C1-C3-haloalkoxy, nitro or hydroxy;    R4 represents hydrogen, halogen, C1-C3-alkyl, C1-C3-haloalkyl, C1-C3-alkoxy, C1-C3-haloalkoxy, nitro, cyano or SF5;    R5 represents hydrogen, halogen, C1-C3-alkyl, C1-C3-haloalkyl, C1-C3-alkoxy, C1-C3-haloalkoxy, nitro or cyano;    wherein R1 and R2 or R2 and R3 are optionally linked to one another in such a way that they jointly form a methylenedioxy, ethylenedioxy, ethyleneoxy, trimethyleneoxy or a group selected from:
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.